Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease.
Exposure to Bisphenol A (BPA) has been associated with the development of nonalcoholic fatty liver disease (NAFLD) but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study was designed to explore whether exposure to BPA-triggered abnormal steatosis and lipid accumulation in the liver could be modulated by miR-192. We showed that male post-weaning C57BL/6 mice exposed to 50μg/kg/day of BPA by oral gavage for 90days displayed a NAFLD-like phenotype. In addition, we found in mouse liver and human HepG2 cells that BPA-induced hepatic steatosis and lipid accumulation were associated with decreased expression of miR-192, upregulation of SREBF1 and a series of genes involved in de novo lipogenesis. Downregulation of miR-192 in BPA-exposed hepatocytes could be due to defective pre-miR-192 processing by DROSHA. Using HepG2 cells, we further confirmed that miR-192 directly acted on the 3'UTR of SREBF1, contributing to dysregulation of lipid homeostasis in hepatocytes. MiR-192 mimic and lentivirus-mediated overexpression of miR-192 improved BPA-induced hepatic steatosis by suppressing SREBF1. Lastly, we noted that lipid accumulation was not a strict requirement for developing insulin resistance in mice after BPA treatment. In conclusion, this study demonstrated a novel mechanism in which NAFLD associated with BPA exposure arose from alterations in the miR-192-SREBF1 axis.


Overexpression of micro ribonucleic acid-591 inhibits cell proliferation and invasion of malignant pleural mesothelioma cells.
Malignant pleural mesothelioma (MPM) is an aggressive cancer refractory to current therapies. Reduced expression of micro ribonucleic acid (miR)-591 in a range of cancer types has suggested it is a potent tumor suppressor, and overexpression has been shown to inhibit tumor cell growth. The role of miR-591 in MPM is largely unknown. miR-591 was over-expressed in vitro using micro RNA mimics in three MPM cell lines (H513, H2052, H2373), and effects on tumor cell growth, proliferation, invasion, and target gene expression were assessed. miR-591 mimic was introduced into MPM cell lines to overexpress this microRNA. The cellular growth, proliferation, and invasive capability was significantly inhibited after overexpression of miR-591. Growth inhibition caused by miR-591 correlated with upregulation of p21 and Bax. Reduced invasive capability correlated with downregulation of matrix metalloproteinase-2 and transforming growth factor-β1. miR-591 is a potent tumor suppressor in MPM. Overexpression of miR-591 may represent a novel therapeutic approach for MPM.


An N-terminal motif in NLR immune receptors is functionally conserved across distantly related plant species.
The molecular codes underpinning the functions of plant NLR immune receptors are poorly understood. We used in vitro Mu transposition to generate a random truncation library and identify the minimal functional region of NLRs. We applied this method to NRC4-a helper NLR that functions with multiple sensor NLRs within a Solanaceae receptor network. This revealed that the NRC4 N-terminal 29 amino acids are sufficient to induce hypersensitive cell death. This region is defined by the consensus MADAxVSFxVxKLxxLLxxEx (MADA motif) that is conserved at the N-termini of NRC family proteins and ~20% of coiled-coil (CC)-type plant NLRs. The MADA motif matches the N-terminal α1 helix of Arabidopsis NLR protein ZAR1, which undergoes a conformational switch during resistosome activation. Immunoassays revealed that the MADA motif is functionally conserved across NLRs from distantly related plant species. NRC-dependent sensor NLRs lack MADA sequences indicating that this motif has degenerated in sensor NLRs over evolutionary time.


Population estimation and trappability of the European badger (Meles meles): implications for tuberculosis management.
Estimates of population size and trappability inform vaccine efficacy modelling and are required for adaptive management during prolonged wildlife vaccination campaigns. We present an analysis of mark-recapture data from a badger vaccine (Bacille Calmette-Guérin) study in Ireland. This study is the largest scale (755 km(2)) mark-recapture study ever undertaken with this species. The study area was divided into three approximately equal-sized zones, each with similar survey and capture effort. A mean badger population size of 671 (SD: 76) was estimated using a closed-subpopulation model (CSpM) based on data from capturing sessions of the entire area and was consistent with a separate multiplicative model. Minimum number alive estimates calculated from the same data were on average 49-51% smaller than the CSpM estimates, but these are considered severely negatively biased when trappability is low. Population densities derived from the CSpM estimates were 0.82-1.06 badgers km(-2), and broadly consistent with previous reports for an adjacent area. Mean trappability was estimated to be 34-35% per session across the population. By the fifth capture session, 79% of the adult badgers caught had been marked previously. Multivariable modelling suggested significant differences in badger trappability depending on zone, season and age-class. There were more putatively trap-wary badgers identified in the population than trap-happy badgers, but wariness was not related to individual's sex, zone or season of capture. Live-trapping efficacy can vary significantly amongst sites, seasons, age, or personality, hence monitoring of trappability is recommended as part of an adaptive management regime during large-scale wildlife vaccination programs to counter biases and to improve efficiencies.


Disability fingerprints: patterns of disability in spinal cord injury and multiple sclerosis differ.
Models for causation of functional disability differ as to whether different diseases lead to common expressions of disability versus producing unique "disability fingerprints." Multiple sclerosis (MS) and Spinal Cord Injury (SCI) both affect the spinal cord; however, their pathophysiologies differ (progressive vs. nonprogressive; multifocal vs. unifocal). Patterns of disability were compared among veterans who reported in a national survey that they had MS (n = 1789) or SCI (n = 6361) as the sole cause of their spinal cord dysfunction. The study used self-reported information on disease duration, physical impairments, and self-care skills to compare the two samples for differences in disability overall and after stratification according to (a) disease duration, and (b) specific physical impairments. Patterns of disability differed significantly among persons with MS compared to SCI (p = .001). Differences in level of disability between the two samples remained statistically significant after stratification on disease duration. There were substantial, statistically significant differences between the two samples in the amount and kinds of physical impairment. However, differences in level of disability between the two conditions remained highly significant after stratifying on number of affected limbs (p = .003), amount of useful movement (p = .001), overall motor impairment (p = .003), amount of sensation (p = .001), impairment in memory and thinking (p = .001), and visual impairment (p = .001). This study shows differing diseases indeed have unique disability fingerprints, which remain unique after controlling for disease duration and for population-specific differences in physical impairment. These findings point out the need to explain the disablement process more fully.


Characteristics of the ichthyofauna of a temperate microtidal estuary with a reverse salinity gradient, including inter-decadal comparisons.
Data on the fish fauna of the Leschenault Estuary on the lower west coast of Australia were collected and used as a model to elucidate the characteristics of permanently open estuaries with a reverse salinity gradient, which undergo seasonal changes similar to many other estuaries with Mediterranean climate. Focus was placed on determining (1) the relationships of the number of species, density, life cycle category and species composition of fishes with region (within estuary), season and year and salinity, (2) whether species are partitioned along the lengths of such systems and (3) the extent and significance of any inter-decadal changes in species composition. The analyses and interpretation involved using multi-factorial permutational multivariate analysis of variance (PERMANOVA) and analysis of similarity (ANOSIM) designs, and three new or recently published visualization tools, i.e. modified non-metric multidimensional scaling (nMDS) plots, coherent species curves and segmented bubble plots. The base, lower, upper and apex regions of the Leschenault Estuary, along which the salinity increased in each season except in winter when most rainfall occurs, were sampled seasonally for the 2 years between winter 2008 and autumn 2010. Estuarine residents contributed twice as many individuals, but less than half the number of species as marine taxa. While the numbers of marine species and estuarine residents declined between the base or lower and apex regions, the individuals of marine species dominated the catches in the base region and estuarine residents in the other three regions. Ichthyofaunal composition in each region underwent conspicuous annual cyclical changes, due to time-staggered differences in recruitment among species, and changed sequentially along the estuary, both paralleling salinity trends. Different groups of species characterized the fauna in the different regions and seasons, thereby partitioning resources among species. The ichthyofauna of the apex region, in which salinities reached 54 and temperatures 36° C, recorded the highest maximum density and, in terms of abundance, was dominated (90%) by three atherinid species, emphasizing the ability of this family to tolerate extreme conditions. Comparisons between the data for 2008-2010 and 1994 demonstrate that the spotted hardyhead Craterocephalus mugiloides and the common hardyhead Atherinomorus vaigiensis had colonized and become abundant in the Leschenault Estuary in the intervening period. This represents a southwards extension of the distribution of these essentially tropical species during a period of increasing coastal water temperatures as a result of climate change. The abundance of weed-associated species, e.g. the western gobbleguts Ostorhinchus rueppellii and the soldier Gymnapistes marmoratus, increased, whereas that of the longfinned goby Favonigobius lateralis decreased, probably reflecting increases in eutrophication and siltation, respectively.


Encapsulation of proteins in biodegradable polymeric microparticles using electrospray in the Taylor cone-jet mode.
Solvent extraction (or evaporation from a W(1)/O/W(2)-dispersion), coacervation, and spray drying methods are commonly employed to encapsulate protein drugs in polymeric microparticles for sustained delivery applications. To overcome the limitations of these methods, a novel electrospray method was developed to encapsulate a model protein drug-bovine serum albumin (BSA) in biodegradable polymeric microparticles and examine the feasibility of the process in not denaturing the protein. Microparticles of approximately 20 microm diameter with corrugated surfaces and smooth surfaces were observed by scanning electron microscope. Confocal laser scanning microscope images showed that BSA was distributed evenly in microparticles. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was employed to investigate the protein integrity of BSA released from the polymer matrix after 38 days. No protein degradation was observed during the 38 days release. The secondary structure of released BSA was characterized by Fourier transform infrared (FTIR) and circular dichroism (CD), which suggested that the released BSA was almost identical to native BSA. The encapsulation efficiency could reach 76% by adjusting the amount of the additive Pluronic F127 and processing parameters. The release profile could be tailored by the fabrication process and the sustained release of BSA could endure for more than 1 month. More than 80% of the bioactivity of BSA (evaluated by BSA ELISA kit) could be maintained after releasing from polymer matrix. Findings of the present study demonstrate that this novel electrospray method is a promising approach to encapsulate bioactive materials such as proteins, enzymes, antibiotics, and DNA fragments in biodegradable polymeric particles.


Middle Pliocene hominin diversity: Australopithecus deyiremeda and Kenyanthropus platyops.
Geometric morphometric shape analyses are used to compare the maxillae of the Kenyanthropus platyops holotype KNM-WT 40000, the Australopithecus deyiremeda holotype BRT-VP-3/1 and other australopiths. The main aim is to explore the relationship between these two specimens and contemporary Australopithecus afarensis Five landmarks placed on lateral views of the maxillae quantify key aspects of the morphology. Generalized Procrustes analyses and principal component analyses of the resulting shape coordinates were performed. The magnitudes of differences in shape and their significances were assessed using Procrustes and Mahalanobis' distances, respectively. Both KNM-WT 40000 and BRT-VP-3/1 show statistically significant differences in maxillary shape from A. afarensis, but do so in dissimilar ways. Moreover, the former differs more from A. afarensis than the latter. KNM-WT 40000 has a more anteriorly positioned zygomatic process with a transversely flat, and more orthognathic subnasal clivus. BRT-VP-3/1 has a more inferiorly positioned zygomatic process, a slightly retracted dental arcade, but without shortening of the anterior maxilla. These findings are consistent with previous conclusions that the two fossils should be attributed to separate species, rather than to A. afarensis, and with the presence of three contemporary hominin species in the Middle Pliocene of eastern Africa.This article is part of the themed issue 'Major transitions in human evolution'.


Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults.
There are conflicting data on the natural history and clinical significance of bone marrow lesions (BMLs). The aims of this study were to describe the natural history of MRI-detected BMLs at the knee using a quantitative measure and examine the association of BMLs with pain, function and stiffness scores, and total knee replacement (TKR) surgery. A total of 395 older males and females were randomly selected from the general population (mean age 63 years, range 52 to 79) and measured at baseline and approximately 2.7 years later. BMLs were determined using T2-weighted fat saturation MRI by measuring the maximum area of the lesion. Reproducibility was excellent (intraclass correlation coefficient (ICC): 0.97). Pain, function, and stiffness were assessed by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores. X-ray was used to assess radiographic osteoarthritis (ROA) at baseline. At baseline, 43% (n = 168/395) had a BML. Of these 25% decreased in size and 24% increased. Of the remaining sample (n = 227), 7% developed a new BML. In a multivariable model, a change in BML size was associated with a change in pain and function scores (β = 1.13 to 2.55 per 1 SD increase, all P < 0.05), only in those participants without ROA. Lastly, baseline BML severity predicted TKR surgery (odds ratio (OR) 2.10/unit, P = 0.019). In a population based sample, BMLs (assessed by measuring maximal area) were not static, with similar proportions both worsening and improving. A change in BML size was associated with changes in pain in those without established ROA. This finding suggests that fluctuating knee pain may be attributable to BMLs in those participants with early stage disease. Baseline BMLs also predicted TKR surgery. These findings suggest therapeutic interventions aimed at altering the natural history of BMLs should be considered.


A comparative study of biodegradation of vinyl acetate by environmental strains.
Four Gram-negative strains, E3_2001, EC1_2004, EC3_3502 and EC2_3502, previously isolated from soil samples, were subjected to comparative studies in order to select the best vinyl acetate degrader for waste gas treatment. Comparison of biochemical and physiological tests as well as the results of fatty acids analyses were comparable with the results of 16S rRNA gene sequence analyses. The isolated strains were identified as Pseudomonas putida EC3_2001, Pseudomonas putida EC1_2004, Achromobacter xylosoxidans EC3_3502 and Agrobacterium sp. EC2_3502 strains. Two additional strains, Pseudomonas fluorescens PCM 2123 and Stenotrophomonas malthophilia KB2, were used as controls. All described strains were able to use vinyl acetate as the only source of carbon and energy under aerobic as well as oxygen deficiency conditions. Esterase, alcohol dehydrogenase and aldehyde dehydrogenase were involved in vinyl acetate decomposition under aerobic conditions. Shorter degradation times of vinyl acetate were associated with accumulation of acetic acid, acetaldehyde and ethanol as intermediates in the culture fluids of EC3_2001 and KB2 strains. Complete aerobic degradation of vinyl acetate combined with a low increase in biomass was observed for EC3_2001 and EC1_2004 strains. In conclusion, P. putida EC1_2004 is proposed as the best vinyl acetate degrader for future waste gas treatment in trickle-bed bioreactors.


Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells.
Pancreatic cancer has a poor prognosis even when complete resection can be accomplished. Recent studies have demonstrated that the immune system is capable of mounting effective tumor-specific immune responses even against "nonimmunogenic" tumors. The studies reported herein were conducted to determine if induction of tumor-specific immune responses of inhibiting in vivo pancreatic tumor growth could be achieved through active immunization with pancreatic tumor cells genetically engineered to secrete interleukin-2 (IL-2). A relevant poorly immunogenic subcutaneous model of murine ductal pancreatic cancer was first developed using an implantable tumor cell line Panc02 in C57BL/6 mice. Panc02 cells were then genetically engineered to secrete human IL-2 (Panc02/IL2). The ability of irradiated Panc02/IL2 cells to stimulate an immune response capable of rejecting a subsequent tumor challenge was first demonstrated. Ninety percent of animals vaccinated with irradiated parental Panc02 and subsequently challenged with parental Panc02 cells developed tumors by 48 days (mean tumor volume of 234 mm3) compared to only 40% (P < .05, chi square) of animals vaccinated with irradiated Panc02/IL2 and challenged with parental Panc02 (14 mm3, P < .004, tau test). The therapeutic benefit of active immunization in tumor-bearing animals was then examined. Mice with 3-day-old established subcutaneous tumors were administered a series of 4 weekly vaccinations with irradiated Panc02 or Panc02/IL2 cells. A significant reduction in tumor growth was present in those animals vaccinated with Panc02/IL2 (P < .005, tau test) versus Panc02 or saline. Animals whose established tumors regressed following vaccinations with IL-2-secreting Panc02 cells were found to have long-lasting immunity as demonstrated by rejection of a tumor challenge presented over 140 days following inoculation of the primary tumor. We conclude that an immune response capable of inhibiting established pancreatic tumors can be generated by vaccination with IL-2-secreting tumor cells. Furthermore, long-term immunological memory was established in mice that rejected the original established tumor. These studies provide preclinical evidence to support the use of cytokine gene-transduced tumor cell vaccinations in patients with pancreatic cancer.


Hope and caution: rewilding to mitigate the impacts of biological invasions.
Rewilding is a novel approach to ecological restoration. Trophic rewilding in particular aims to reinstate ecological functions, especially trophic interactions, through the introduction of animals. We consider the potential for trophic rewilding to address biological invasions. In this broad review, we note some of the important conceptual and ethical foundations of rewilding, including a focus on ecosystem function rather than composition, reliance on animal agency, and an appeal to an ethic of coexistence. Second, we use theory from invasion biology to highlight pathways by which rewilding might prevent or mitigate the impacts of an invasion, including increasing biotic resistance. Third, we use a series of case studies to illustrate how reintroductions can mitigate the impacts of invasions. These include reintroductions and positive management of carnivores and herbivores including European pine martens (Martes martes), Eurasian otters (Lutra lutra), dingoes (Canis dingo), Tasmanian devils (Sarcophilus harrisii) and tule elk (Cervus canadensis nannodes). Fourth, we consider the risk that rewilding may enable a biological invasion or aggravate its impacts. Lastly, we highlight lessons that rewilding science might take from invasion biology.This article is part of the theme issue 'Trophic rewilding: consequences for ecosystems under global change'.


Principal components of heritability for high dimension quantitative traits and general pedigrees.
For many complex disorders, genetically relevant disease definition is still unclear. For this reason, researchers tend to collect large numbers of items related directly or indirectly to the disease diagnostic. Since the measured traits may not be all influenced by genetic factors, researchers are faced with the problem of choosing which traits or combinations of traits to consider in linkage analysis. To combine items, one can subject the data to a principal component analysis. However, when family date are collected, principal component analysis does not take family structure into account. In order to deal with these issues, Ott & Rabinowitz (1999) introduced the principal components of heritability (PCH), which capture the familial information across traits by calculating linear combinations of traits that maximize heritability. The calculation of the PCHs is based on the estimation of the genetic and the environmental components of variance. In the genetic context, the standard estimators of the variance components are Lange's maximum likelihood estimators, which require complex numerical calculations. The objectives of this paper are the following: i) to review some standard strategies available in the literature to estimate variance components for unbalanced data in mixed models; ii) to propose an ANOVA method for a genetic random effect model to estimate the variance components, which can be applied to general pedigrees and high dimensional family data within the PCH framework; iii) to elucidate the connection between PCH analysis and Linear Discriminant Analysis. We use computer simulations to show that the proposed method has similar asymptotic properties as Lange's method when the number of traits is small, and we study the efficiency of our method when the number of traits is large. A data analysis involving schizophrenia and bipolar quantitative traits is finally presented to illustrate the PCH methodology.


Variation in physiological host range in three strains of two species of the entomopathogenic fungus Beauveria.
Knowledge of the host range of a biocontrol agent (BCA) is fundamental. Host range determines the BCA's economic potential, as well as the possible risk for non-target organisms. Entomopathogenic fungal strains belonging to the genus Beauveria are widely used as BCA, but our knowledge of their physiological host range is only partial. The aim of this study was to improve our understanding of the physiological host range of three Beauveria strains belonging to two species, B. hoplocheli and B. bassiana. We performed laboratory mortality bioassays to assess their pathogenicity and virulence against nine insect pests, belonging to three orders: Lepidoptera, Coleoptera and Diptera. Mortality rate, mean survival time and mycosis rate were used to estimate virulence. Pathogenicity was assessed as the capacity to cause a disease and induce mortality. Virulence was assessed as the severity of the disease based on mortality rate, mean survival time and mycosis rate. The results of this study revealed significant differences in the physiological host range of the three Beauveria strains tested. The three strains were pathogenic to all Diptera and Lepidoptera species tested. In the case of the Coleoptera, only the B. hoplocheli strain was pathogenic to the white grub Hoplochelus marginalis and only the B. bassiana strains were pathogenic to Alphitobius diaperinus. The B. hoplocheli strain was less virulent on Lepidoptera and Diptera than the two B. bassiana strains. The latter both exhibited very similar virulence patterns. The fact that B. hoplocheli and B. bassiana strains have different host ranges means that they can be used as BCA to target different pests. Impacts on non-target insects across multiple orders cannot be ruled out in the absence of ecological host range studies.


Dorsomedial Prefrontal Cortex Repetitive Transcranial Magnetic Stimulation for Tinnitus: Promising Results of a Blinded, Randomized, Sham-Controlled Study.
Tinnitus is the perception of sound in ears or head without corresponding external stimulus. Despite the great amount of literature concerning tinnitus treatment, there are still no evidence-based established treatments for curing or for effectively reducing tinnitus intensity. Sham-controlled studies revealed beneficial effects using repetitive transcranial magnetic stimulation (rTMS). Still, results show moderate, temporary improvement and high individual variability. Subcallosal area (ventral and dorsomedial prefrontal and anterior cingulate cortices) has been implicated in tinnitus pathophysiology. Our objective is to evaluate the use of bilateral, high frequency, dorsomedial prefrontal cortex (DMPFC) rTMS in treatment of chronic subjective tinnitus. Randomized placebo-controlled, single-blinded clinical trial. Twenty sessions of bilateral, 10 Hz rTMS at 120% of resting motor threshold of extensor hallucis longus were applied over the DMPFC. Fourteen patients underwent sham rTMS and 15 were submitted to active stimulation. Tinnitus Handicap Inventory (THI), visual analog scale, and tinnitus loudness matching were obtained at baseline and on follow-up visits. The impact of intervention on outcome measures was evaluated using mixed-effects restricted maximum likelihood regression model for longitudinal data. A difference of 11.53 points in the THI score was found, favoring the intervention group (p = 0.05). The difference for tinnitus loudness matching was of 4.46 dB also favoring the intervention group (p = 0.09). Tinnitus treatment with high frequency, bilateral, DMPFC rTMS was effective in reducing tinnitus severity measured by THI and matched tinnitus loudness when compared to sham stimulation.


Microscopic and macroscopic polarization within a combined quantum mechanics and molecular mechanics model.
A polarizable quantum mechanics and molecular mechanics model has been extended to account for the difference between the macroscopic electric field and the actual electric field felt by the solute molecule. This enables the calculation of effective microscopic properties which can be related to macroscopic susceptibilities directly comparable with experimental results. By separating the discrete local field into two distinct contribution we define two different microscopic properties, the so-called solute and effective properties. The solute properties account for the pure solvent effects, i.e., effects even when the macroscopic electric field is zero, and the effective properties account for both the pure solvent effects and the effect from the induced dipoles in the solvent due to the macroscopic electric field. We present results for the linear and nonlinear polarizabilities of water and acetonitrile both in the gas phase and in the liquid phase. For all the properties we find that the pure solvent effect increases the properties whereas the induced electric field decreases the properties. Furthermore, we present results for the refractive index, third-harmonic generation (THG), and electric field induced second-harmonic generation (EFISH) for liquid water and acetonitrile. We find in general good agreement between the calculated and experimental results for the refractive index and the THG susceptibility. For the EFISH susceptibility, however, the difference between experiment and theory is larger since the orientational effect arising from the static electric field is not accurately described.


Challenges in the recruitment of adolescents and young adults to cancer clinical trials.
The adolescent and young adult (AYA) oncology population has seen inferior progress in cancer survival compared with younger children and older adults over the past 25 years. Previously, AYAs had the best survival rates due to the prevalence of highly curable diseases including Hodgkin lymphoma and germ cell tumors, yet today AYAs have inferior survival rates to children and some adult cohorts. Survival rates are particularly poor for AYA-specific diseases such as sarcomas. Research involving children and adults diagnosed with common malignancies such as acute lymphoblastic leukemia has resulted in improved survival rates. However, AYAs have not directly benefited from such research due to low rates of access to and accrual on clinical trials. AYAs are less likely to have insurance or access to healthcare, are more likely to see providers who are not part of research institutions, and are less likely to be referred to or to join clinical trials, all of which may contribute to worse outcomes. Few clinical trials target AYA-specific diseases, leading to little information regarding how these diseases behave and what role the host plays. Tumor samples for this population are underrepresented in national tumor banks. Coupled with the need for more clinical trials that focus on AYA-specific cancers, better collaboration between adult and pediatric cooperative groups as well as increased education among community oncologists and primary care providers will be needed to enhance participation in clinical trials with the goal to increase survival and improve quality of that survival.


Chondroitinase: A promising therapeutic enzyme.
Even after 20 years of granting orphan status for chondroitinase by US FDA, there is no visible outcome in terms of clinical use. The reasons are many. One of them could be lack of awareness regarding the biological application of the enzyme. The biological activity of chondroitinase is due to its ability to act on chondroitin sulfate proteoglycans (CSPGs). CSPGs are needed for normal functioning of the body. An increase or decrease in the level of CSPGs results in various pathological conditions. Chondroitinase is useful in conditions where there is an increase in the level of CSPGs, namely spinal cord injury, vitreous attachment and cancer. Over the last decade, various animal studies showed that chondroitinase could be a good drug candidate. Research focusing on developing a suitable carrier system for delivering chondroitinase needs to be carried out so that pharmacological activity observed in vitro and preclinical studies could be translated to clinical use. Further studies on distribution of chondroitinase as well need to be focused so that chondroitinase with desired attributes could be discovered. The present review article discusses about various biological applications of chondroitinase, drug delivery systems to deliver the enzyme and distribution of chondroitinase among microbes.


Tunable dual-comb from an all-polarization-maintaining single-cavity dual-color Yb:fiber laser.
We demonstrate dual-comb generation from an all-polarization-maintaining dual-color ytterbium (Yb) fiber laser. Two pulse trains with center wavelengths at 1030 nm and 1060 nm respectively are generated within the same laser cavity with a repetition rate around 77 MHz. Dual-color operation is induced using a tunable mechanical spectral filter, which cuts the gain spectrum into two spectral regions that can be independently mode-locked. Spectral overlap of the two pulse trains is achieved outside the laser cavity by amplifying the 1030-nm pulses and broadening them in a nonlinear fiber. Spatially overlapping the two arms on a simple photodiode then generates a down-converted radio frequency comb. The difference in repetition rates between the two pulse trains and hence the line spacing of the down-converted comb can easily be tuned in this setup. This feature allows for a flexible adjustment of the tradeoff between non-aliasing bandwidth vs. measurement time in spectroscopy applications. Furthermore, we show that by fine-tuning the center-wavelengths of the two pulse trains, we are able to shift the down-converted frequency comb along the radio-frequency axis. The usability of this dual-comb setup is demonstrated by measuring the transmission of two different etalons while the laser is completely free-running.


Simulation of tissue-prosthesis margin interface by using surface scanning and digital design for auricular prostheses.
One of the most challenging aspects of auricular prosthesis design and fabrication is ensuring that the prosthesis fits the patient through a range of head and facial movements. Techniques used in conventional prosthetic treatment pathways account for issues of prosthesis fit, but this challenge has not been fully addressed in emerging treatment pathways that use digital technology. The purpose of this clinical study was to develop and evaluate a digital workflow by using surface scan data and incorporating the simulation of tissue movement into the design of auricular prostheses that fit the participant through a range of facial movements. An iterative design process was used to develop a design workflow through a sequential case series of participants with auricular prostheses. Scan data were acquired from a case series of 5 participants with existing implant-retained auricular prostheses. An iterative design process was used to digitally design auricular prostheses that fit the participants through a range of jaw and facial movements. The fit, shape, and retention of the digitally designed and conventionally made prostheses were assessed and compared. Design considerations were identified and documented through the iterative design process. A final design workflow was iteratively developed based on the 5 participants. The shapes of the digitally designed prostheses were well matched to nontreatment anatomy overall. Prosthesis fit was variable: Some digitally designed prostheses fit the participant intimately through a range of movements, and others experienced significant gaps between the margins and the tissues. An iterative design process provided a method of working toward quality improvement. Although the final design workflow provides a generally successful method of manipulating scan data in the design of auricular prostheses, the prosthesis fit at the anterior margin during facial movements remains variable and requires further development to achieve a consistently acceptable solution.


Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.
Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients. In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period. The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening. The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).


Dissipation of Three Veterinary Antimicrobials in Beef Cattle Feedlot Manure Stockpiled over Winter.
Dissipation of veterinary antimicrobials is known to occur during aerated windrow composting of beef cattle manure. However, it is unclear if a similar dissipation occurs during stockpiling. Chlortetracycline, tylosin, and sulfamethazine are three of the most commonly used veterinary antimicrobials in beef cattle production in western Canada. Their dissipation in stockpiled manure was investigated over 140 d during winter in Alberta, Canada. Beef cattle housed in pens were administered 44 mg of chlortetracycline kg feed (dry weight), 44 mg of chlortetracycline + 44 mg sulfamethazine kg feed, 11 mg of tylosin kg feed, or feed without antimicrobials (control). Manure samples were extracted using pressurized liquid extraction, and the extracts were analyzed for chlortetracycline, sulfamethazine, and tylosin by LC-MS-MS. Dissipation of all three antimicrobials in the manure was explained by exponential decay kinetics. Times for 50% dissipation (DT) were 1.8 ± 0.1 d for chlortetracycline alone or 6.0 ± 0.8 d when mixed with sulfamethazine, 20.8 ± 3.8 d for sulfamethazine, and 4.7 ± 1.2 d for tylosin. After 77 d, <1% of initial chlortetracycline and <2% of sulfamethazine remained. Tylosin residues were more variable, decreasing to approximately 12% of initial levels after 28 d, with 20% present after 77 d and 13% after 140 d. Temperatures within stockpiles reached maximum values within 6 d of establishment and varied with location (bottom, 62.5°C; middle, 63.8°C; and top, 42.9°C). Antimicrobials in the manure did not inhibit microbial activity, as indicated by temperature and mass losses of carbon (C) and nitrogen (N). The C/N ratio in the manure decreased over the stockpiling period, indicating decomposition of manure to a more stable state. Dissipation of excreted residues with DT values 1.8 to 20.8 d showed that stockpiling can be as effective as windrow composting in mitigating the transfer of these three veterinary antimicrobials into the environment during land application of processed manure.


Molecular Imprinting Applications in Forensic Science.
Producing molecular imprinting-based materials has received increasing attention due to recognition selectivity, stability, cast effectiveness, and ease of production in various forms for a wide range of applications. The molecular imprinting technique has a variety of applications in the areas of the food industry, environmental monitoring, and medicine for diverse purposes like sample pretreatment, sensing, and separation/purification. A versatile usage, stability and recognition capabilities also make them perfect candidates for use in forensic sciences. Forensic science is a demanding area and there is a growing interest in molecularly imprinted polymers (MIPs) in this field. In this review, recent molecular imprinting applications in the related areas of forensic sciences are discussed while considering the literature of last two decades. Not only direct forensic applications but also studies of possible forensic value were taken into account like illicit drugs, banned sport drugs, effective toxins and chemical warfare agents in a review of over 100 articles. The literature was classified according to targets, material shapes, production strategies, detection method, and instrumentation. We aimed to summarize the current applications of MIPs in forensic science and put forth a projection of their potential uses as promising alternatives for benchmark competitors.


Changes in sex difference in swimming speed in finalists at FINA World Championships and the Olympic Games from 1992 to 2013.
This study investigated swimming speeds and sex differences of finalists competing at the Olympic Games (i.e. 624 female and 672 male athletes) and FINA World Championships (i.e. 990 women and 1008 men) between 1992 and 2013. Linear, non-linear and multi-level regression models were used to investigate changes in swimming speeds and sex differences for champions and finalists. Regarding finalists in FINA World Championships and Olympic Games, swimming speed increased linearly in both women and men in all disciplines and race distances. Male world champions' swimming speed remained stable in 200 m butterfly, 400 m, 800 m and 1,500 m freestyle. Considering women, swimming speed remained unchanged in 50 m and 400 m freestyle. In the Olympic Games, swimming speed of male champions remained unchanged in 200 m breaststroke, 50 m, 400 m, 800 m and 1,500 m freestyle. Female Olympic champions' swimming speed remained stable in 100 m and 200 m backstroke, 100 m butterfly, 200 m individual medley, 50 m and 200 m freestyle. Evaluating sex differences between finalists in FINA World Championships, results showed a linear decrease in 100 m breaststroke and 200 m butterfly and a non-linear increase in 100 m backstroke. In finals at the Olympic Games, the sex difference decreased linearly for 100 m backstroke, 400 m and 800 m freestyle. However, a linear increase for 200 m butterfly can be reported. Considering Olympic and world champions, the sex difference remained stable in all disciplines and race distances. Swimming speed of the finalists at the Olympic Games and FINA World Championships increased linearly. The top annual female swimmers increased swimming speed rather at longer race distances (i.e. 800 m and 1,500 m freestyle, 200 m butterfly, and 400 m individual medley), whereas the top annual male swimmers increased it rather at shorter race distances (i.e. 100 m and 200 m freestyle, 100 m butterfly, and 100 m breaststroke). Sex difference in swimming was unchanged in Olympic and world champions. Finalists and champions at the Olympic Games and FINA World Championships reduced the sex difference with increasing race distance.


Characteristics and homogeneity of N6-methylation in human genomes.
A novel DNA modification, N-6 methylated deoxyadenosine (m6dA), has recently been discovered in eukaryotic genomes. Despite its low abundance in eukaryotes, m6dA is implicated in human diseases such as cancer. It is therefore important to precisely identify and characterize m6dA in the human genome. Here, we identify m6dA sites at nucleotide level, in different human cells, genome wide. We compare m6dA features between distinct human cells and identify m6dA characteristics in human genomes. Our data demonstrates for the first time that despite low m6dA abundance, the m6dA mark does often occur consistently at the same genomic location within a given human cell type, demonstrating m6dA homogeneity. We further show, for the first time, higher levels of m6dA homogeneity within one chromosome. Most m6dA are found on a single chromosome from a diploid sample, suggesting inheritance. Our transcriptome analysis not only indicates that human genes with m6dA are associated with higher RNA transcript levels but identifies allele-specific gene transcripts showing haplotype-specific m6dA methylation, which are implicated in different biological functions. Our analyses demonstrate the precision and consistency by which the m6dA mark occurs within the human genome, suggesting that m6dA marks are precisely inherited in humans.


Political science. Exposure to ideologically diverse news and opinion on Facebook.
Exposure to news, opinion, and civic information increasingly occurs through social media. How do these online networks influence exposure to perspectives that cut across ideological lines? Using deidentified data, we examined how 10.1 million U.S. Facebook users interact with socially shared news. We directly measured ideological homophily in friend networks and examined the extent to which heterogeneous friends could potentially expose individuals to cross-cutting content. We then quantified the extent to which individuals encounter comparatively more or less diverse content while interacting via Facebook's algorithmically ranked News Feed and further studied users' choices to click through to ideologically discordant content. Compared with algorithmic ranking, individuals' choices played a stronger role in limiting exposure to cross-cutting content.


Plasma adrenomedullin levels in patients on hemodialysis.
Adrenomedullin (AM) is a hypotensive peptide that has recently been isolated from human pheochromocytoma. In this study, we measured plasma AM concentrations in 54 patients on hemodialysis (HD) and examined the clinical significance. We also evaluated the effects of high-flux and low-flux dialysis membranes on plasma AM levels. The average value of plasma AM at pre-HD (4.44 +/- 0.16 fmol/ml) was significantly elevated compared with that in 44 healthy volunteers (1.31 +/- 1.41 fmol/ml) (p < 0.0001). The plasma AM concentrations at pre-HD showed a negative correlation with age and mean blood pressure (MBP) at pre-HD. The plasma AM concentrations at post-HD showed a negative correlation with MBP at post-HD and a negative correlation with the reduction rate of AM. Multiple regression analysis showed that age and MBP were independent factors associated with plasma AM at pre-HD and that MBP and reduction rate of AM were independent factors associated with plasma AM at post-HD. We investigated the differences between high-flux dialyzers (PS-UW, PS-N and FB-F) and a low-flux dialyzer (AM-BC-F), and we found that high-flux dialyzers removed plasma AM more efficiently than a low-flux dialyzer did. In addition, in 3 patients on HD, plasma AM levels decreased significantly during isovolumic dialysis using a high-flux dialyzer, despite the fact that there were no significant changes in MBP and ANP. In conclusion, elevation in plasma AM level causes a fall in MBP in patients on HD, therefore, removal of AM by HD treatment using a high-flux dialyzer contributes to the stability of blood pressure during HD.


Four-cycle high-dose therapy with hematopoietic support for metastatic breast cancer: no improvement in outcomes compared with single-course high-dose therapy.
Multiple-cycle high-dose therapy with autologous hematopoietic progenitor cell (AHPC) support has been used to deliver dose-intensive therapy. We have used this approach as well as single-cycle high-dose therapy in treating patients with metastatic breast cancer. We present the outcomes of multiple-cycle high-dose therapies and compare them with those resulting from single-course high-dose therapies performed at a single institution. Fifty-five patients received 4 cycles of intensive chemotherapy with AHPC support. Three multicycle regimens were sequentially applied. Twenty patients were enrolled to receive 4 cycles of high-dose mitoxantrone, thiotepa, and cyclophosphamide. Nineteen subsequent patients received this regimen modified by the incorporation of paclitaxel. Sixteen patients received 2 cycles of high-dose melphalan, thiotepa, and paclitaxel and 2 cycles of mitoxantrone, thiotepa, and paclitaxel. The results of all 3 multiple-cycle therapies are compared with those of 55 contemporaneous patients with metastatic breast cancer who received a single course of high-dose cyclophosphamide and thiotepa or cyclophosphamide, cisplatin, and BCNU (carmustine) with hematopoietic cell rescue. Multiple-cycle therapy was associated with more infectious complications, increased transfusion requirements, and increased hospital admissions. However, there were no significant differences in outcomes between the groups. For 55 patients who received multiple-cycle therapy, the actuarial 3-year overall survival rate was 36% (95% confidence interval [CI] 23%-49%); freedom from progression and event-free survival were both 15% (CI 5%-25%). The median time to disease progression and median survival were 1.0 and 1.6 years, respectively. For the 55 patients who underwent a single course of high-dose therapy, the 3-year overall survival was also 36% (CI 18%-54%), whereas freedom from progression and event-free survival were both 19% (CI 7%-31%). The median time to progression and median survival were 0.8 and 2.2 years, respectively. Within the constraints of this patient population, the outcomes of 4 cycles of high-dose therapy with AHPC support were not superior to those resulting from single courses of high-dose therapy in the treatment of patients with metastatic breast cancer.


Visiting a forest, but not a city, increases human natural killer activity and expression of anti-cancer proteins.
We previously reported that a forest bathing trip enhanced human NK activity, number of NK cells, and intracellular anti-cancer proteins in lymphocytes. In the present study, we investigated how long the increased NK activity lasts and compared the effect of a forest bathing trip on NK activity with a trip to places in a city without forests. Twelve healthy male subjects, age 35-56 years, were selected with informed consent. The subjects experienced a three-day/two-night trip to forest fields and to a city, in which activity levels during both trips were matched. On day 1, subjects walked for two hours in the afternoon in a forest field; and on day 2, they walked for two hours in the morning and afternoon, respectively, in two different forest fields; and on day 3, the subjects finished the trip and returned to Tokyo after drawing blood samples and completing the questionnaire. Blood and urine were sampled on the second and third days during the trips, and on days 7 and 30 after the trip, and NK activity, numbers of NK and T cells, and granulysin, perforin, and granzymes A/B-expressing lymphocytes in the blood samples, and the concentration of adrenaline in urine were measured. Similar measurements were made before the trips on a normal working day as the control. Phytoncide concentrations in forest and city air were measured. The forest bathing trip significantly increased NK activity and the numbers of NK, perforin, granulysin, and granzyme A/B-expressing cells and significantly decreased the concentration of adrenaline in urine. The increased NK activity lasted for more than 7 days after the trip. In contrast, a city tourist visit did not increase NK activity, numbers of NK cells, nor the expression of selected intracellular anti-cancer proteins, and did not decrease the concentration of adrenaline in urine. Phytoncides, such as alpha-pinene and beta-pinene were detected in forest air, but almost not in city air. These findings indicate that a forest bathing trip increased NK activity, number of NK cells, and levels of intracellular anti-cancer proteins, and that this effect lasted at least 7 days after the trip. Phytoncides released from trees and decreased stress hormone may partially contribute to the increased NK activity.


A novel ANCOVA design for analysis of MEG data with application to a visual attention study.
Statistical inference from MEG-based distributed activation maps is well suited to the general linear modeling framework, a standard approach to the analysis of fMRI and PET neuroimaging studies. However, there are important differences from the other neuroimaging modalities related to how observations are created and fitted in GLM models, as well as how subsequent statistical inference is performed. In this paper, we demonstrate how MEG oscillatory components can be analyzed in this framework based on a custom ANCOVA model that takes into account baseline and inter-hemispheric effects, rather than a simpler ANOVA design. We present the methodology using as an example an MEG study of visual spatial attention, since the model design depends on the specific experiment and neuroscience hypotheses being tested. However, the techniques presented here can be readily adapted to accommodate other experimental paradigms. We create statistics that estimate the temporal evolution of attention effects on alpha power in several cortical regions. We present evidence for direction-specific attention effects on alpha activity in occipital and parietal regions and demonstrate the sub-second timing of these effects in each region. The results support a mechanism for anticipatory attentional deployment that dynamically modulates the local alpha synchrony in a network of parietal control and occipital sensory regions.


Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC.
Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals. However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection. Viral genome analysis revealed close relatedness to coronaviruses found in bats. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.


Health status, service use, and costs among veterans receiving outreach services in jail or community settings.
This study compared client characteristics, service use, and health care costs of two groups of veterans who were contacted by outreach workers: a group of veterans who were contacted while incarcerated at the Los Angeles jail and a group of homeless veterans who were contacted in community settings. Between May 1, 1997, and October 1, 1999, a total of 1,676 veterans who were in jail and 6,560 community homeless veterans were assessed through a structured intake procedure that documented their demographic, clinical, and social adjustment characteristics. Data on the use and costs of health services during the year after outreach contact were obtained from national databases of the Department of Veterans Affairs (VA). Chi square and t tests were used for statistical comparisons. The veterans who were contacted in jail obtained higher scores on several measures of social stability (marital status and homelessness status) but had higher rates of unemployment. They had fewer medical problems but higher levels of psychiatric and substance use problems, although the rate of current substance use was lower among these veterans than among the community homeless veterans. One-year service access for the jailed veterans was half that of the community homeless veterans. No differences were observed in the intensity of use of mental health services among those who used services, but the jailed outreach clients used fewer residential, medical, and surgical services. Total health care expenditures for the veterans who received outreach contact in jail were $2,318 less, or 30 percent less, than for those who were contacted through community outreach. Specialized outreach services appear to be modestly effective in linking veterans who become incarcerated with VA health care services. Although it is clinically challenging to link this group with services, the fact that the rate of current substance use is lower during incarceration may provide a window of opportunity for developing linkages between inmates and community rehabilitative services.


Experimental modulation of occluding junctions in a cultured transporting epithelium.
The experimental opening and resealing of occluding junctions in monolayers of cultured MDCK cells (epithelioid of renal origin) was explored by measuring changes in the electrical resistance across the monolayer and by freeze-fracture electron microscopy. As in natural epithelia, the function of occluding junctions as permeability barriers specifically depends on extracellular Ca++ concentration and fails if this ion is replaced by Mg++ or Ba++. The removal of Ca++ and the addition of EGTA to the bathing medium opened the junctions and reduced the transepithelial resistance. Resealing was achieved within 10-15 min by restoring Ca++. Quantitative freeze-fracture electron microscopy showed that junctional opening, caused by lack of Ca++, was accompanied by simplification of the pattern of the membrane strands of the occluding junction without disassembly or displacement of the junctional components. Resealing of the cellular contacts involved the gradual return to a normal junctional pattern estimated as the average number of strands constituting the junction. The occluding junctions were also opened by the addition of the ionophore A23187, suggesting that the sealing of the contacts requires high Ca++ on the extracellular side and low Ca++ concentration of the cytoplasmic compartment. The opening process could be blocked by low temperature (7.5 degrees C). Resealing did not depend on serum factors and did not require protein synthesis; therefore, it seems to be caused by reassembly of preexisting membrane junctional components. The restoration of the junctions occurred simultaneously with the establishment of ion-selective channels; the Na+/Cl- and the cation/cation selectivity were recovered with the same time-course as the electrical resistance. The role of the cytoskeleton in the process of junctional reassembly is reported in the companion article.


Temperament and its Association with Autism Symptoms in a High-risk Population.
Temperament was investigated in a group of high-risk infants (N = 383; 45 % girls) who had an older sibling with autism spectrum disorder (ASD), and in community control infants (N = 162; 46 % girls) with no family history of ASD (low-risk). The infants were assessed at age 12 months using the Infant Behavior Questionnaire, and at 24 months using the Toddler Behavior Assessment Questionnaire. At 36 months, an independent blind diagnostic assessment for ASD was conducted using the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). The results indicate not only differences in temperament traits between the high- and low-risk groups, but also differences in the structure of higher-order temperament factors. The results support the importance of early reactive temperament in the development of Effortful Control in the high-risk sample. Furthermore, Effortful Control at 24 months appears to play a critical role in predicting later ASD symptoms (at 36 months). Taken together, these findings support the use of early temperament as an endophenotype for ASD.


Suaeda vermiculata Aqueous-Ethanolic Extract-Based Mitigation of CCl4-Induced Hepatotoxicity in Rats, and HepG-2 and HepG-2/ADR Cell-Lines-Based Cytotoxicity Evaluations.
Suaeda vermiculata, an edible halophytic plant, used by desert nomads to treat jaundice, was investigated for its hepatoprotective bioactivity and safety profile on its mother liquor aqueous-ethanolic extract. Upon LC-MS (Liquid Chromatography-Mass Spectrometry) analysis, the presence of several constituents including three major flavonoids, namely quercetin, quercetin-3-O-rutinoside, and kaempferol-O-(acetyl)-hexoside-pentoside were confirmed. The aqueous-ethanolic extract, rich in antioxidants, quenched the DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals, and also showed noticeable levels of radical scavenging capacity in ABTS (2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid) assay. For the hepatoprotective activity confirmation, the male rat groups were fed daily, for 7 days (n = 8/group, p.o.), either carboxyl methylcellulose (CMC) 0.5%, silymarin 200 mg/kg, the aqueous-ethanolic extract of the plant Suaeda vermiculata (100, 250, and 500 mg/kg extract), or quercetin (100 mg/kg) alone, and on day 7 of the administrations, all the animal groups, excluding a naïve (250 mg/kg aqueous-ethanolic extract-fed), and an intact animal group were induced hepatotoxicity by intraperitoneally administering carbon tetrachloride (CCl4). All the animals were sacrificed after 24 h, and aspartate transaminase and alanine transaminase serum levels were observed, which were noted to be significantly decreased for the aqueous-ethanolic extract, silymarin, and quercetin-fed groups in comparison to the CMC-fed group (p < 0.0001). No noticeable adverse effects were observed on the liver, kidney, or heart's functions of the naïve (250 mg/kg) group. The aqueous-ethanolic extract was found to be safe in the acute toxicity (5 g/kg) test and showed hepatoprotection and safety at higher doses. Further upon, the cytotoxicity testings in HepG-2 and HepG-2/ADR (Adriamycin resistant) cell-lines were also investigated, and the IC50 values were recorded at 56.19±2.55 µg/mL, and 78.40±0.32 µg/mL (p < 0.001, Relative Resistance RR 1.39), respectively, while the doxorubicin (Adriamycin) IC50 values were found to be 1.3±0.064, and 4.77±1.05 µg/mL (p < 0.001, RR 3.67), respectively. The HepG-2/ADR cell-lines when tested in a combination of the aqueous-ethanolic extract with doxorubicin, a significant reversal in the doxorubicin's IC50 value by 2.77 folds (p < 0.001, CI = 0.56) was noted as compared to the cytotoxicity test where the extract was absent. The mode of action for the reversal was determined to be synergistic in nature indicating the role of the aqueous-ethanolic extract.


Morphology and life history divergence in cave and surface populations of Gammarus lacustris (L.).
Cave animals provide a unique opportunity to study contrasts in phenotype and life history in strikingly different environments when compared to surface populations, potentially related to natural selection. As such, we compared a permanent cave-living Gammarus lacustris (L.) population with two lake-resident surface populations analyzing morphology (eye- and antennal characters) and life-history (size at maturity, fecundity and egg-size). A part of the cytochrome c oxidase subunit I gene in the mitochondrion (COI) was analyzed to contrast genetic relationship of populations and was compared to sequences in GenBank to assess phylogeography and colonization scenarios. In the cave, a longer life cycle was implied, while surface populations seemed to have a shorter life cycle. Egg size, and size at maturity for both sexes, were larger in the cave than in surface populations, while fecundity was lower in the cave than in surface populations. The cave population had longer first- and second antennae with more articles, longer first- and second peduncles, and fewer ommatidia than surface populations. The cold low-productive cave environment may facilitate different phenotypic and life-history traits than in the warmer and more productive surface lake environments. The trait divergences among cave and surface populations resembles other cave-surface organism comparisons and may support a hypothesis of selection on sensory traits. The cave and Lake Ulvenvann populations grouped together with a sequence from Slovenia (comprising one genetic cluster), while Lake Lille Lauarvann grouped with a sequence from Ukraine (comprising another cluster), which are already recognized phylogenetic clusters. One evolutionary scenario is that the cave and surface populations were colonized postglacially around 9 000-10 000 years ago. We evaluate that an alternative scenario is that the cave was colonized during an interstadial during the last glaciation or earlier during the warm period before onset of the last glaciation.


Prevalence of Falls and Fall-Related Outcomes in Older Adults with Self-Reported Vision Impairment.
To determine the prevalence of falls, fear of falling (FoF), and activity limitation due to FoF in a nationally representative study of older adults with self-reported vision impairment (VI). Cross-sectional analysis of panel survey data. National Health and Aging Trends Study, a nationally representative survey administered annually from 2011 to 2016 to U.S. Medicare beneficiaries aged 65 and older. Respondents (N=11,558) who contributed 36,229 participant observations. We performed logistic regression to calculate the unadjusted and adjusted prevalence of self-reported history of more than 1 fall in the past year, any fall in the past month, FoF, and activity limitation due to FoF in participants with and without self-reported VI. The weighted proportion of participants reporting VI was 8.6% (95% confidence interval (CI)=8.0-9.2%). The unadjusted prevalence of more than 1 fall in the past year was 27.6% (95% CI=25.5-29.7%) in participants with self-reported VI and 13.2% (95% CI=12.7-13.7%) in those without self-reported VI. In respondents with self-reported VI, the prevalence of FoF was 48.3% (95% CI=46.1-50.6%) and of FoF limiting activity was 50.8% (95%CI 47.3-54.2%), and in those without self-reported VI, the prevalence of FoF was 26.7% (95% CI=25.9-27.5%) and of FoF limiting activity was 33.9% (95% CI=32.4-35.4%). The prevalence of all fall and fall-related outcomes remained significantly higher among those with self-reported VI after adjusting for sociodemographics and potential confounders. The prevalence of falls, FoF, and activity limitation due to FoF is high in older adults with self-reported VI. This is the first study to provide nationally representative data on the prevalence of fall-related outcomes in older Americans with self-reported VI. These findings demonstrate the need to treat avoidable VI and to develop interventions to prevent falls and fall-related outcomes in this population. J Am Geriatr Soc 67:239-245, 2019.


Amide synthesis from alcohols and amines catalyzed by ruthenium N-heterocyclic carbene complexes.
The direct synthesis of amides from alcohols and amines is described with the simultaneous liberation of dihydrogen. The reaction does not require any stoichiometric additives or hydrogen acceptors and is catalyzed by ruthenium N-heterocyclic carbene complexes. Three different catalyst systems are presented that all employ 1,3-diisopropylimidazol-2-ylidene (IiPr) as the carbene ligand. In addition, potassium tert-butoxide and a tricycloalkylphosphine are required for the amidation to proceed. In the first system, the active catalyst is generated in situ from [RuCl(2)(cod)] (cod=1,5-cyclooctadiene), 1,3-diisopropylimidazolium chloride, tricyclopentylphosphonium tetrafluoroborate, and base. The second system uses the complex [RuCl(2)(IiPr)(p-cymene)] together with tricyclohexylphosphine and base, whereas the third system employs the Hoveyda-Grubbs 1st-generation metathesis catalyst together with 1,3-diisopropylimidazolium chloride and base. A range of different primary alcohols and amines have been coupled in the presence of the three catalyst systems to afford the corresponding amides in moderate to excellent yields. The best results are obtained with sterically unhindered alcohols and amines. The three catalyst systems do not show any significant differences in reactivity, which indicates that the same catalytically active species is operating. The reaction is believed to proceed by initial dehydrogenation of the primary alcohol to the aldehyde that stays coordinated to ruthenium and is not released into the reaction mixture. Addition of the amine forms the hemiaminal that undergoes dehydrogenation to the amide. A catalytic cycle is proposed with the {(IiPr)Ru(II)} species as the catalytically active components.


Variability of total and pathogenic Vibrio parahaemolyticus densities in northern Gulf of Mexico water and oysters.
Vibrio parahaemolyticus is indigenous to coastal environments and a frequent cause of seafood-borne gastroenteritis in the United States, primarily due to raw-oyster consumption. Previous seasonal-cycle studies of V. parahaemolyticus have identified water temperature as the strongest environmental predictor. Salinity has also been identified, although it is evident that its effect on annual variation is not as pronounced. The effects of other environmental factors, both with respect to the seasonal cycle and intraseasonal variation, are uncertain. This study investigated intraseasonal variations of densities of total and pathogenic V. parahaemolyticus organisms in oysters and overlying waters during the summer of 2004 at two sites in the northern Gulf of Mexico. Regression analyses indicated significant associations (P < 0.001) between total V. parahaemolyticus densities and salinity, as well as turbidity in water and in oysters at the Mississippi site but not at the Alabama site. Pathogenic V. parahaemolyticus organisms in Mississippi oyster and water samples were detected in 56% (9 out of 16) and 78% (43 out of 55) of samples, respectively. In contrast, 44% (7 out of 16) of oyster samples and 30% (14 out of 47) of water samples from Alabama were positive. At both sites, there was greater sample-to-sample variability in pathogenic V. parahaemolyticus densities than in total V. parahaemolyticus densities. These data suggest that, although total V. parahaemolyticus densities may be very informative, there is greater uncertainty when total V. parahaemolyticus densities are used to predict the risk of infection by pathogenic V. parahaemolyticus than previously recognized.


In vivo genome editing using a high-efficiency TALEN system.
The zebrafish (Danio rerio) is increasingly being used to study basic vertebrate biology and human disease with a rich array of in vivo genetic and molecular tools. However, the inability to readily modify the genome in a targeted fashion has been a bottleneck in the field. Here we show that improvements in artificial transcription activator-like effector nucleases (TALENs) provide a powerful new approach for targeted zebrafish genome editing and functional genomic applications. Using the GoldyTALEN modified scaffold and zebrafish delivery system, we show that this enhanced TALEN toolkit has a high efficiency in inducing locus-specific DNA breaks in somatic and germline tissues. At some loci, this efficacy approaches 100%, including biallelic conversion in somatic tissues that mimics phenotypes seen using morpholino-based targeted gene knockdowns. With this updated TALEN system, we successfully used single-stranded DNA oligonucleotides to precisely modify sequences at predefined locations in the zebrafish genome through homology-directed repair, including the introduction of a custom-designed EcoRV site and a modified loxP (mloxP) sequence into somatic tissue in vivo. We further show successful germline transmission of both EcoRV and mloxP engineered chromosomes. This combined approach offers the potential to model genetic variation as well as to generate targeted conditional alleles.


Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro.
Modulation of the growth of human and murine cell lines in vitro by recombinant human tumor necrosis factor-alpha (rTNF-alpha) and recombinant human interferon-gamma (rIFN-gamma) was investigated. rTNF-alpha had cytostatic or cytolytic effects on only some tumor cell lines. When administered together with rIFN-gamma, rTNF-alpha showed enhanced antiproliferative effects on a subset of the cell lines tested. In contrast to its effects on sensitive tumor cells, rTNF-alpha augmented the growth of normal diploid fibroblasts. Variations in the proliferative response induced by rTNF-alpha were apparently not due to differences in either the number of binding sites per cell or their affinity for rTNF-alpha. These observations indicate that the effects of rTNF-alpha on cell growth are not limited to tumor cells, but rather that this protein may have a broad spectrum of activities in vivo.


Serological pattern consistent with infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult offspring.
Previous studies have shown that maternal antibodies to Toxoplasma measured during pregnancy are associated with an increased risk of schizophrenia and other psychoses in adult offspring. Recently, it has been recognized that different genotypes of Toxoplasma have distinct neuropathogenic potential. The objective of this study was to investigate whether parasite genotype is a contributing factor to disease risk. We have developed an enzyme-linked immunosorbent assay (ELISA) that uses polymorphic polypeptides specific to the three clonal parasite lineages and derived from three dense granule antigens, GRA5, GRA6 and GRA7. We used this assay to measure type-specific antibodies in the sera from 219 pregnant women whose children developed schizophrenia and affective psychotic illnesses in adult life, and 618 matched unaffected control mothers from three cohorts of the Collaborative Perinatal Project. We found that the offspring of mothers with a serological pattern consistent with Toxoplasma type capital I, Ukrainian infection were at significantly increased risk for the development of psychoses as compared with the matched unaffected control mothers (odds ratio=1.94; 95% confidence interval=1.08-3.46; p=0.03). The risk was particularly elevated for affective psychoses (OR=5.24; 95% CI=1.67-16.5; p=0.005). In contrast, we did not find an association between maternal antibodies to other genotypes and risk of psychoses in the offspring. These findings suggest an influence of the parasite genotype on increased risk of psychosis and provide further support for a substantive role of Toxoplasma in the etiology of psychosis.


A Collision Risk Model to Predict Avian Fatalities at Wind Facilities: An Example Using Golden Eagles, Aquila chrysaetos.
Wind power is a major candidate in the search for clean, renewable energy. Beyond the technical and economic challenges of wind energy development are environmental issues that may restrict its growth. Avian fatalities due to collisions with rotating turbine blades are a leading concern and there is considerable uncertainty surrounding avian collision risk at wind facilities. This uncertainty is not reflected in many models currently used to predict the avian fatalities that would result from proposed wind developments. We introduce a method to predict fatalities at wind facilities, based on pre-construction monitoring. Our method can directly incorporate uncertainty into the estimates of avian fatalities and can be updated if information on the true number of fatalities becomes available from post-construction carcass monitoring. Our model considers only three parameters: hazardous footprint, bird exposure to turbines and collision probability. By using a Bayesian analytical framework we account for uncertainties in these values, which are then reflected in our predictions and can be reduced through subsequent data collection. The simplicity of our approach makes it accessible to ecologists concerned with the impact of wind development, as well as to managers, policy makers and industry interested in its implementation in real-world decision contexts. We demonstrate the utility of our method by predicting golden eagle (Aquila chrysaetos) fatalities at a wind installation in the United States. Using pre-construction data, we predicted 7.48 eagle fatalities year-1 (95% CI: (1.1, 19.81)). The U.S. Fish and Wildlife Service uses the 80th quantile (11.0 eagle fatalities year-1) in their permitting process to ensure there is only a 20% chance a wind facility exceeds the authorized fatalities. Once data were available from two-years of post-construction monitoring, we updated the fatality estimate to 4.8 eagle fatalities year-1 (95% CI: (1.76, 9.4); 80th quantile, 6.3). In this case, the increased precision in the fatality prediction lowered the level of authorized take, and thus lowered the required amount of compensatory mitigation.


Differential association of drinking motives with alcohol use on weekdays and weekends.
Drinking motives (DM) reflect the reasons why individuals drink alcohol. Weekdays are mainly dedicated to work, whereas weekends are generally associated with spending time with friends during special events or leisure activities; using alcohol on weekdays and weekends may also be related to different DM. This study examined whether DM were differentially associated with drinking volume (DV) on weekdays and weekends. A representative sample of 5,391 young Swiss men completed a questionnaire assessing weekday and weekend DV, as well as their DM, namely, enhancement, social, coping, and conformity motives. Associations of DM with weekday and weekend DV were examined using structural equation models. Each DM was tested individually in a separate model; all associations were positive and generally stronger (except conformity) for weekend rather than for weekday DV. Further specific patterns of association were found when DM were entered into a single model simultaneously. Associations with weekday and with weekend DV were positive for enhancement and coping motives. However, associations were stronger with weekend rather than with weekday DV for enhancement, and stronger with weekday than with weekend DV for coping motives. Associations of social motives were not significant with weekend DV and negative with weekday DV. Conformity motives were negatively associated with weekend DV and positively related to weekday DV. These results suggest that interventions targeting enhancement motives should be particularly effective at decreasing weekend drinking, whereas interventions targeted at coping motives would be particularly effective at reducing alcohol use on weekdays.


Novel expression of neuropeptide Y (NPY) mRNA in hypothalamic regions during development: region-specific effects of maternal deprivation on NPY and Agouti-related protein mRNA.
During development there is novel expression of NPY mRNA in the dorsomedial hypothalamic nucleus (DMH) and perifornical region (PFR), in addition to the arcuate nucleus (ARH). Furthermore, NPY mRNA levels peak in all regions on postnatal d 16 (P16) and decrease to adult levels by P30. The purpose of the present study was to determine whether NPY and agouti-related protein (AGRP) mRNA expression in the different hypothalamic regions on P11 and P16 are similarly affected by fasting. An examination of the full rostral to caudal extent of the hypothalamus revealed two additional regions displaying novel NPY mRNA expression, the parvocellular division of the paraventricular nucleus (PVH) and lateral hypothalamus (LH). Maternal deprivation for 36 h, used to bring about a fast, similarly increased (23-29%) NPY and AGRP mRNA expression in the ARH on P11 and P16. In contrast, NPY expression in the DMH and PFR were significantly decreased (19-30% and 48-53%, respectively), whereas NPY mRNA levels in the PVH and LH were not altered by this treatment. The increase in NPY and AGRP mRNA expression in the ARH in response to maternal deprivation suggests that these neuronal populations respond to signals of energy balance. In contrast, NPY expression in the DMH, PFR, PVH, and LH is differentially regulated by maternal deprivation or other factors associated with maternal separation.


Pharmacokinetics of nicotine tartrate after single-dose liquid enema, oral, and intravenous administration.
Ulcerative colitis is predominantly a disease of nonsmokers, and transdermal nicotine is therapeutic but often results in adverse reactions. Colonic administration of nicotine tartrate as a liquid enema could decrease systemic nicotine absorption and adverse reactions. The purpose of the current study was to determine the bioavailability and pharmacokinetic parameters of nicotine after administration by hydrophilic liquid enema (acidic and basic), hydrophobic liquid enema (acidic and basic), and by oral and intravenous routes. Thirty healthy volunteers received 45 micrograms nicotine base/kg (as nicotine tartrate) in one of five formulations (each n = 6): hydrophilic acidic liquid enema, hydrophilic basic liquid enema, hydrophobic acidic liquid enema, hydrophobic basic liquid enema, and oral solution. All participants also received 15 micrograms nicotine base/kg (as nicotine tartrate) intravenously during a separate study period. Serum concentrations of nicotine were determined by gas chromatography with mass spectrometry. The mean (+/-SD) bioavailabilities of nicotine after administration in the liquid enema formulations (hydrophilic acidic 17 +/- 18%, hydrophilic basic 16 +/- 16%, hydrophobic acidic 25 +/- 17%, hydrophobic basic 15 +/- 12%) were similar to the bioavailability of nicotine after administration by oral solution (20 +/- 25%). The bioavailabilities of nicotine for all five nonintravenous formulations were significantly less than for intravenous nicotine (100%). Serum concentrations of nicotine did not predict adverse reactions. Nicotine tartrate administered as either a liquid enema or as an oral solution had low bioavailability and was well tolerated. The therapeutic potential of nicotine tartrate liquid enemas, which can potentially limit toxicity by local (colonic) delivery of high doses of nicotine should be investigated in patients with left-sided ulcerative colitis.


Information flow and optimization in transcriptional regulation.
In the simplest view of transcriptional regulation, the expression of a gene is turned on or off by changes in the concentration of a transcription factor (TF). We use recent data on noise levels in gene expression to show that it should be possible to transmit much more than just one regulatory bit. Realizing this optimal information capacity would require that the dynamic range of TF concentrations used by the cell, the input/output relation of the regulatory module, and the noise in gene expression satisfy certain matching relations, which we derive. These results provide parameter-free, quantitative predictions connecting independently measurable quantities. Although we have considered only the simplified problem of a single gene responding to a single TF, we find that these predictions are in surprisingly good agreement with recent experiments on the Bicoid/Hunchback system in the early Drosophila embryo and that this system achieves approximately 90% of its theoretical maximum information transmission.


High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study.
The aim of the study was to investigate the association of postoperative delirium with the outcomes of cognitive impairment, functional disability and death. Hip surgery patients aged 60 years or over (n = 200) underwent preoperative and daily postoperative assessment of their cognitive status during hospital stay. Outcome variables were determined at an average of 8 and 38 months after discharge from hospital. Fourty-one patients developed postoperative delirium. Delirium was a strong independent predictor of cognitive impairment and the occurrence of severe dependency in activities of daily living. The associations were more marked for the long- than for the short-term outcome. Thirty-eight months after discharge from hospital, 53.8% of the surviving patients with postoperative delirium suffered from cognitive impairment, as compared to only 4.4% of the nondelirious participants. Logistic regression analysis adjusted for age, sex, medical comorbidity and preoperative cognitive performance revealed highly significant associations between delirium and cognitive impairment (OR = 41.2; 95% CI = 4.3-396.2), subjective memory decline (OR = 6.2; 95% CI = 1.5-25.8) and incident need for long-term care (OR = 5.6; 95% CI = 1.6-19.7). The present study confirms a poor prognosis after delirium in elderly patients. The findings suggest that delirium does not simply persist for a certain time but also predicts a future cognitive decline with an increased risk of dementia.


Experiences of Kenyan healthcare workers providing services to men who have sex with men: qualitative findings from a sensitivity training programme.
Men who have sex with men (MSM) in Kenya are at high risk for HIV and may experience prejudiced treatment in health settings due to stigma. An on-line computer-facilitated MSM sensitivity programme was conducted to educate healthcare workers (HCWs) about the health issues and needs of MSM patients. Seventy-four HCWs from 49 ART-providing health facilities in the Kenyan Coast were recruited through purposive sampling to undergo a two-day MSM sensitivity training. We conducted eight focus group discussions (FGDs) with programme participants prior to and three months after completing the training programme. Discussions aimed to characterize HCWs' challenges in serving MSM patients and impacts of programme participation on HCWs' personal attitudes and professional capacities. Before participating in the training programme, HCWs described secondary stigma, lack of professional education about MSM, and personal and social prejudices as barriers to serving MSM clients. After completing the programme, HCWs expressed greater acknowledgement of MSM patients in their clinics, endorsed the need to treat MSM patients with high professional standards and demonstrated sophisticated awareness of the social and behavioural risks for HIV among MSM. Findings provide support for this approach to improving health services for MSM patients. Further efforts are needed to broaden the reach of this training in other areas, address identified barriers to HCW participation and evaluate programme effects on patient and HCW outcomes using rigorous methodology.


Germline BRCA, chemotherapy response scores, and survival in the neoadjuvant treatment of ovarian cancer.
To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated. BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients. In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.


Antitumor activity of Lycium barbarum polysaccharides with different molecular weights: an in vitro and in vivo study.
The antitumor activity of Lycium barbarum polysaccharide (LBP) has been reported, but the structure-bioactivity relationship has still not been fully elucidated. In this study, four water-soluble LBP fractions with serial different molecular weights (MWs) were separated from LBP, designated LBP-2, LBP-3, LBP-4, and LBP-5. After a characteristic analysis, the relationship between MW and antitumor activity of LBP was investigated both in vitro using murine hepatoma H22 cells and in vivo using H22 tumor-bearing mice. In vitro, the results showed that all the LBP fractions had significant inhibition on H22 cells, in which LBP-3 had the best activity. LBP-3 could induce apoptosis, mitochondrial membrane potential destruction, and S phase arrest in H22 cells. In vivo, the results showed that LBP-2, LBP-3, LBP-4, and LBP-5 could inhibit the tumor growth in H22 tumor-bearing mice by 18.18%, 37.97%, 9.09%, and 14.44%, respectively. However, only LBP-3 was able to decrease the tumor weight significantly in H22 tumor-bearing mice. Meanwhile, all the LBP fractions did not show significant toxicity to murine splenocytes, thymus, and spleen. Taken together, these results demonstrated that the antitumor activity of LBP was closely related to its MW, and LBP-3 with medium MW (40-350 kDa) was the main active fraction.


Do social networks influence small-scale fishermen's enforcement of sea tenure?
Resource systems with enforced rules and strong monitoring systems typically have more predictable resource abundance, which can confer economic and social benefits to local communities. Co-management regimes demonstrate better social and ecological outcomes, but require an active role by community members in management activities, such as monitoring and enforcement. Previous work has emphasized understanding what makes fishermen comply with rules. This research takes a different approach to understand what influences an individual to enforce rules, particularly sea tenure. We conducted interviews and used multiple regression and Akaike's Information Criteria model selection to evaluate the effect of social networks, food security, recent catch success, fisherman's age and personal gear investment on individual's enforcement of sea tenure. We found that fishermen's enforcement of sea tenure declined between the two time periods measured and that social networks, age, food security, and changes in gear investment explained enforcement behavior across three different communities on Nicaragua's Atlantic Coast, an area undergoing rapid globalization.


Polarization control of electron tunneling into ferroelectric surfaces.
We demonstrate a highly reproducible control of local electron transport through a ferroelectric oxide via its spontaneous polarization. Electrons are injected from the tip of an atomic force microscope into a thin film of lead-zirconate titanate, Pb(Zr0.2Ti0.8)O3, in the regime of electron tunneling assisted by a high electric field (Fowler-Nordheim tunneling). The tunneling current exhibits a pronounced hysteresis with abrupt switching events that coincide, within experimental resolution, with the local switching of ferroelectric polarization. The large spontaneous polarization of the PZT film results in up to 500-fold amplification of the tunneling current upon ferroelectric switching. The magnitude of the effect is subject to electrostatic control via ferroelectric switching, suggesting possible applications in ultrahigh-density data storage and spintronics.


Interactions of hydrogen with the iron and iron carbide interfaces: a ReaxFF molecular dynamics study.
Hydrogen embrittlement (HE) is a well-known material phenomenon that causes significant loss in the mechanical strength of structural iron and often leads to catastrophic failures. In order to provide a detailed atomistic description of HE we have used a reactive bond order potential to adequately describe the diffusion of hydrogen as well as its chemical interaction with other hydrogen atoms, defects, and the host metal. The currently published ReaxFF force field for Fe/C/H systems was originally developed to describe Fischer-Tropsch (FT) catalysis [C. Zou, A. C. T. van Duin and D. C. Sorescu, Top. Catal., 2012, 55, 391-401], and especially had been trained for surface formation energies, binding energies of small hydrocarbon radicals on different surfaces of iron and the barrier heights of surface reactions. We merged this force field with the latest ReaxFF carbon parameters [S. Goverapet Srinivasan, A. C. T. van Duin and P. Ganesh, J. Phys. Chem. A, 2015, 119, 1089-5639] and used the same training data set to refit the Fe/C interaction parameters. The present work is focused on evaluating the applicability of this reactive force field to describe material characteristics and study the role of defects and impurities in the bulk and at the precipitator interfaces. We study the interactions of hydrogen with pure and defective α-iron (ferrite), Fe3C (cementite), and ferrite-cementite interfaces with a vacancy cluster. We also investigate the growth of nanovoids in α-iron using a grand canonical Monte Carlo (GCMC) scheme. The calculated hydrogen diffusion coefficients for both ferrite and cementite phases predict a decrease in the work of separation with increasing hydrogen concentration at the ferrite-cementite interface, suggesting a hydrogen-induced decohesion behavior. Hydrogen accumulation at the interface was observed during molecular dynamics (MD) simulations, which is consistent with experimental findings. These results demonstrate the ability of the ReaxFF potential to elucidate various aspects of hydrogen embrittlement in α-iron and hydrogen interactions at a more complex metal/metal carbide interface.


Tumor-To-Tumor Metastasis of Poorly Differentiated Gastric Carcinoma to Uterine Lipoleiomyoma.
The rare phenomenon of tumor-to-tumor metastasis was first described in 1930. The donor neoplasm is most frequently lung or breast carcinoma, whereas intracranial meningiomas are reportedly the commonest recipient neoplasm. Here we report a case of metastasis from a primary gastric cancer to a uterine lipoleiomyoma. A 65-year-old woman presented with locally advanced gastric cancer with computed tomography (CT) evidence of peritoneal dissemination and a 9 cm pelvic mass. She underwent 16 courses of TS-1/cisplatin chemotherapy, which achieved significant tumor reduction. However, repeat CT and magnetic resonance imaging revealed a 9 cm diameter pelvic mass adjacent to the uterus. The mass was heterogeneously hyperintense on T1- and T2-weighted images with some low signal spots on fat-suppressed T1-weighted images, suggesting a benign ovarian tumor such as a mature cystic teratoma. After 3 months, pelvic CT revealed a 10 cm multilocular cystic mass that exhibited heterogeneous enhancement after intravenous contrast administration. A diagnostic laparotomy revealed a subserosal uterine tumor extending into the right broad ligament; total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. The uterine tumor showed histological features of lipoleiomyoma infiltrated by well- to moderately differentiated carcinoma cells that were similar to those of the gastric biopsy, supporting a diagnosis of metastatic gastric adenocarcinoma.


The importance of rating scales in measuring patient-reported outcomes.
A critical component that influences the measurement properties of a patient-reported outcome (PRO) instrument is the rating scale. Yet, there is a lack of general consensus regarding optimal rating scale format, including aspects of question structure, the number and the labels of response categories. This study aims to explore the characteristics of rating scales that function well and those that do not, and thereby develop guidelines for formulating rating scales. Seventeen existing PROs designed to measure vision-related quality of life dimensions were mailed for self-administration, in sets of 10, to patients who were on a waiting list for cataract extraction. These PROs included questions with ratings of difficulty, frequency, severity, and global ratings. Using Rasch analysis, performance of rating scales were assessed by examining hierarchical ordering (indicating categories are distinct from each other and follow a logical transition from lower to higher value), evenness (indicating relative utilization of categories), and range (indicating coverage of the attribute by the rating scale). The rating scales with complicated question format, a large number of response categories, or unlabelled categories, tended to be dysfunctional. Rating scales with five or fewer response categories tended to be functional. Most of the rating scales measuring difficulty performed well. The rating scales measuring frequency and severity demonstrated hierarchical ordering but the categories lacked even utilization. Developers of PRO instruments should use a simple question format, fewer (four to five) and labelled response categories.